Inman Anti-Seizure Phrmacology

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Side Effects

Kidney Stones

Zonisamide Topiramate

ride rollercoasters in the Top Zone amusement park to pass kidney stones

Aplastic Anemia

Carbamazepine Felbamate

Ane felt too Feeble to play with her Plastic Car

Aplastic Anemia --> felbamate + carba

Teratogenic

Carbamazepine Valproic Acid/Valproate/Divalproex

Val got in the Car 🚗--> accident --> lost her baby --> teratogenic

Weight

Gain: Valproic acid, sodium valproate, divalproex Gabapentin/Pregabalin

Val Gambled & got Pregnant 🤰 (i.e. gained weight)

Loss: Zonisamide Topiramate

gonna find me a Top Zaddy once I lose weight

Stevens-Johnson syndrome

Lamotrigine Phenobarbital

Steven & Johnson are Lame Barbs

Hepatotoxicity

Carbamazepine Phenobarbital Vigabatrin Valproic Acid/Valproate, Divalproex Felbamate

Can Phineas & Ferb be Hip (Hepato) Victorious Vigilantes

Hyponatremia (retention of water)

All iminostilbenes: -Carbamazepine -Ocarba -Escli

Can't Escape Overwatering = water retention = hyponatremia

Inman Anti-Seizure Phrmacology

• Seizure: disordered, synchronous and rhythmic firing of neurons
• leading theory is that it's caused by activity-dependent reduction of inhibition
• inc inhibition or dec excitation is the cornerstone of seizure management
• Epilepsy: disorder characterized by periodic and unpredictable seizures

Unknown mechanism

Cannabidiol

Well tolerated, AEs are diarrhea, and sleepiness -seizures asso. w/ lennox-gastaut or dravet

5-HT2 Modulation

Fenfluramine

-Stimulation of 5-HT to increase GABA activity

Binding to SV2A

Levetriacetam/Briva

-Reduce NT release -well absorbed, not metabolized, few DDI

Many Mechanism: Drugs

Topiramate

Broad spec, approved for migraine, multiple MOA -inhibits CYP2C9 -kidney stones, weight loss -cleft palate in newborns

Felbamate

Broad spectrum, multiple MOA -inhibits CYP2C19, CYP3A4 -aplastic anemia (black box), hepatic failure -reserved for extreme refractory epilepsies (esp lennox-gastaut syndrome)

Divalproex/Valproic Acid/Sodium Valproate

Broad-spectrum, multiple potential MOA -highly bound to plasma protein -inhibits CYP2C9, UGT (DDI w/ pheny, pheno, lamotrigine, lorazepine) -weight gain, teratogenicity, liver toxicity (Rare/fatal)

Neurotransmitters

Ion Channels

Inhibition of Ca channel a2g

Drugs: Gaba/pregaba

Pregabalin 3-10x more potent -does NOT mimic GABA effects -not metabolized, not bound to protein, no DDI, well tolerated -weight gain

Potassium Channel Opener

Ezogabine: -adj + alt for partial seizure Unique MOA: Neuronal KCNQ/Kv7 K channel opener

ADE: QT prolongation, blue skin discoloration, retina pigment changes

Na Channel Blockers (inactivation, reduce excitation)

Other drugs: Primadone (not much to say)

Zonisamide: -works on both Na/T-type Ca channels -Kidney stones, weight loss, oligohidrosis

Rufinamide: -When all else fails, use this May increase convulsion in some pts.

Phenytoin/Fosphenytoin: -narrow therapeutic window -Gingival hyperplasia -skin thickening; hirsutism; acne

Lamotrigine: -1st/2nd line for most seizures, broad spectrum -metabolism inhibited by UGT (DDI valproate) -Stevens-Johnson syndrome/rash

Lacosamide: -1st line partial seizures -Class V controlled

MOA: Slow recovery of voltage-gated Na Channels in neurons

-Iminostilbenes (zepines)

Oxca/Eslic: good/complete oral absorption -hyponatremia -less potent inducer of liver enzymes/no autoinduction

Carba: slow/erratic oral absorption -autoinducer (aka it induces its own metabolism = lower blood conc. at higher doses) -Asplastic anemia, leukopenia, hepatic toxicity, teratogenicity, hyponatremia

Blockade of T-Type Ca Channels (reduce excitation)

Drugs: Valproic acid and ethosuximide are T-channel blockers, they reduce excitation

Ethox: -effective against absence (only use) GI disturbances

-Absence seizure has high levels of T-type Ca channel

Drug Action on Ion Channels and Neuronal activity

Excitatory

Aspartic acid

Glutamic acid

Drug: Perampanel - Glutamate/AMPA receptor antagonist -90% protein bound, many DDI -Partial + generalized seizures

Activation leads to: -inc influx of Ca/Na -member depolarization -encourages generation of action potential

Inhibitory

Glycine

GABA

GABAergic Agents

Stiripentol: only used as adj for driver syndrome w/ clobazam

Vigabatrin: -1st line for infantile spasm, adj for partial seizures -may aggravate seizures + psychiatric effects in pts. w/ depression, psychosis -progressively reduces visual field in high % of pts, hepatotoxicity

Tiagabine: -95% protein bound -inc incidence of seizures and status epileptics

Phenobarbital/Primadone (also Na blocker)

Pheno: -has the least sedative effect in its class -long half-life (5 days), induces CYP/UGT -v strong sedation, cog impairment, behavioral changes -hepatotoxicity, SJS, toxic epidermal necrolysis, risk of dependence

BZDs: Clobazam, Clonazepam, Diazepam, Lorazepam -Reserved for emergency due to tolerance -MOA: Positive allosteric modulators of GABA-A, increase freq of GABA-Activated Cl channel opening

Lorazepam/diazepam 1st line for status epileptics (IV) -Abrupt DC of clobazam may cause withdrawal symptoms (convulsions, psychosis, hallucinations, anxiety, tremor)

GABA-A is a Cl channel -Activation inhibits the action potential